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To be or SCA27B? That is the Question: Mystery ataxia cases solved by advances in genetic technology

Written by Dr. Hayley McLoughlin and Dr. Sharan Srinivasan
Edited by Dr. Celeste Suart

A novel genetic sequencing technology uncovered numerous familial ataxia cases linked to a unique mutation in an old genetic ataxia culprit.

Despite improved access to genetic testing, the ability to diagnose hereditary ataxias remains quite difficult. This is especially true in late-onset ataxia cases. As such, a large number of affected individuals remain undiagnosed. The human genome was first sequenced in 2003 using short sequencing technologies. This allowed for the decoding of the majority of the human genome. However, it wasn’t until the last half-decade that long-read sequencing technology filled in the missing pieces of the human genome.  Scientists are now able to explore newly documented regions of the human genome for discrepancies in a disease population relative to a control population. 

For ataxia gene hunters, advancements in long-read sequencing have brought about many new discoveries in these late-onset cerebellar ataxias that previously resisted molecular diagnosis. In parallel papers, Rafehi et al. 2022 and Pellerin et al. 2022 use long-read sequencing to interrogate undiagnosed late-onset cerebellar ataxias. Both research teams found repetitive repeat expansion (>300 GAA repeats) in the intronic sequence of fibroblast growth factor 14 (FGF14). Between these two papers, repeat expansions in the FGF14 gene were found in over 200 patients within late-onset cerebellar ataxias patient cohorts defining a new subtype known as SCA27B.

Interestingly,  a different kind of mutation in FGF14 has previously been reported to cause SCA27A. SCA27A is a dominantly inherited ataxia presenting with nystagmus, gait difficulties, and tremor. In some rare cases, there can also be an intellectual developmental delay.  SCA27A is largely considered to be caused by a loss of the FGF14 protein in brain regions that regulate movement. Previous studies in a mouse model lacking Fgf14 showed a loss of Purkinje neurons, the critical motor cell in the cerebellum. It was also noted that these mice had impaired neuronal circuitry, and FGF14 is thought to play a role in the proper transport and assembly of ion channels. In SCA27B patients, Pellerin et al. described a similar loss of FGF14 protein in postmortem SCA27B patient brain tissues and iPSC neuronal cell culture model. Whether a repeat expansion in FGF14 results in a similar circuit disorder remains unclear, but ion channels may be a desirable target for intervention, as in other SCAs.

However, despite affecting the same gene, there are slight differences between SCA27A and SCA27B symptoms. The patients described in the two SCA27B papers all had a fairly similar clinical presentation: downbeat nystagmus (or “bouncing” of the eyes) followed by decreases in coordination. Symptoms in SCA27B typically start happening after age 50. In all cases, patients demonstrated irreversible progression of their symptoms. In the study by Rafehi and colleagues, the age at which patients first experience symptoms went down as the number of repeats they had increased (about ~1 year for every 10 repeats above 250).  This means the more repeats someone has, the younger they are when they start to have balance problems.

Other SCA27B symptoms that were described by the researchers include muscle stiffness, dizziness, tremors, and nerve damage. One patient even had parkinsonism. While the details remain unclear, variations in repeat length likely drive clinical heterogeneity – put more simply, why there are so many different combinations of symptoms. For example, between generations, there are several instances where offspring have significantly less severe or more severe symptoms. This may be due to contraction (when passed by the father) or expansion (when passed by the mother) of the repeat, respectively.

Worldwide prevalence of SCA has been approximately 1-5 in 100,000 people, with SCA3 being the most common. The two SCA27B papers suggest that SCA27B may be even more frequent in the population. For example, Pellerin and colleagues found the prevalence of the FGF14 repeat expansion within late-onset cerebellar ataxia cohorts was:

  • 61% in their French-Canadian cohort (40/66 patients)
  • 18% in their German cohort (42/228 patients)
  • 15% in their Australian cohort (3/20 patients)
  • 10% in their Indian cohort (3/31 patients).

As more patients are diagnosed, the actual frequency will become clearer, possibly surpassing SCA3 for the most common SCA.

As is well known to SCAsource readers, there are currently no FDA-approved medications for any spinocerebellar ataxia, though many ongoing studies are dedicated to this effort. In the paper by Pellerin and colleagues, they describe a partial response by some SCA27B patients to 4-aminopyridine, a known potassium channel blocker that is often used in the treatment of downbeat nystagmus. This finding is of great interest, not only because 4-aminopyridine is currently clinically available, but because it suggests that the circuit-based issues seen in SCA27A (see above) may be similarly contributory in SCA27B.

The discovery of SCA27B signifies a radical shift in our approach and study of hereditary ataxias. First, a large number of previously undiagnosed patients will now have an explanation. Second, the proposed high prevalence will ensure that significant resources are dedicated to basic science and clinical research into the disease. Third, uncovering an intronic repeat expansion leading to an autosomal dominant inheritance forces us to consider previously less-studied genetic causes of disease.

The future of SCA27B is likely to be fast-paced and exhilarating. While the two papers summarized here establish some basic fundamentals, numerous questions still remain. Most important is the clinical prevalence and ability to diagnose remaining mystery patients. Currently, repeat expansion testing of FGF14 is only available on a research basis. Developing a laboratory test that meets government regulations for clinical use is a high priority.

The discovery and development of therapeutic interventions will require model systems and an improved understanding of the biological basis for disease. Mouse models and patient-derived stem cell models using neurons and organoids are sure to be priorities for basic science researchers.

However, there is no model system better than the human patient. Understanding the clinical trajectory of these patients is critical as we enter a clinical-trial readiness phase for many SCAs. Developing SCA27B longitudinal natural history studies will also be vital to ready patients for future interventions. Brain donations for future comparison of petri-dish-based models to those afflicted with the actual disease are an invaluable resource for both scientific and clinical researchers. The combined efforts of patients, caregivers, clinicians, and laboratory researchers are sure to advance our understanding and, hopefully, our ability to treat this new disease.

Key Words

Short-Read Sequencing: A method of reading the DNA code within a short sequence, generally between 75-150 base pairs.

Long-Read Sequencing: A newer method of reading the DNA code in longer chunks, typically between 10,000 and 100,000 base pairs long.

Natural History Study: A clinical study about a disease which involves multiple examinations of patients at defined time points. This often includes objective findings such as imaging, blood work, or even spinal fluid, to better define the disease course and identify biomarkers of the disease.

Conflict of Interest Statement

The author and editor declare no conflict of interest.

Citation of Articles Reviewed

Pellerin, D. et al. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. New Engl J Med 388, 128–141 (2022).

Rafehi, H. et al. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14. Am J Hum Genetics 110, 105–119 (2023).


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